13 June 2017 EMA/CHMP/ICH/3943/2003 Committee for Human Medicinal Products
ICH guideline E2B (R3) - questions and answers Step 5
Transmission to CHMP for adoption
July 2017
Release for information
July 2017
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact
An agency of the European Union
© European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.
Document History Code E2B(R3)
History Approval by the ICH Steering Committee under
Date 12 November
Q&As
Step 4
2014
Approval by the ICH Assembly under Step 4
16 June 2016
Approval by the ICH Assembly under Step 4
10 November
Version 1.0 E2B(R3) Q&As Version 1.1 E2B(R3) Q&As
2016
Version 2.0 E2B(R3)
Approval by the ICH Assembly under Step 4
1 June 2017
Q&As Version 2.1
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 2/31
ICH guideline E2B (R3) - questions and answers Table of contents Preface ........................................................................................................ 4 1. Purposes ................................................................................................. 4 2. Background ............................................................................................. 4 3. Essential Components ............................................................................. 5 4. ICH E2B(R3) data elements ................................................................... 10 5. Document attachment ........................................................................... 18 6. The ICSR acknowledgement transaction ............................................... 19 7. Appendices ............................................................................................ 19 8. Q&As merged into the implementation guide ........................................ 19 9. Q&As linked to the respective Sections of ICH E2B(R3) Guideline ......... 24
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 3/31
Preface This Q&A document provides clarifications for the harmonized interpretation of the E2B(R3) IG package and should be reviewed in conjunction with the IG package. This will facilitate the implementation of the electronic transmission of Individual Case Safety Reports (ICSRs) in the ICH regions. The sections of this Q&A document corresponds to the organization of the E2B(R3) IG. Pharmaceutical companies, regulators and vendors are encouraged to submit implementation-related questions to the ICH E2B(R3) EWG/IWG; answers to these questions are developed by the ICH E2B(R3) EWG/IWG in accordance with the ICH consensus process. Questions concerning the time frame and specific regional requirements not communicated in the E2B(R3) guidance are answered in guidance documents published for each region. The use of the terminology “upgrading” or “downgrading” in the documents included in the IG package refers to the technical conversion between E2B(R2) and E2B(R3). Future update to this Q&A document, if any, will be published at ICH web site.
1. Purposes No Q&A
2. Background No Q&A
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 4/31
3. Essential Components #
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) 3.1
November
Does ICH data type “AN” accept
In principle, ICH “AN” data type accepts all characters, including space
(001)
2014
Space?
and some special characters listed in UTF8, but some characters such as > and < are not allowed with XML message. So please refer to section
Does ICH data type “AN” accept
3.6 of the ICH ICSR Implementation Guide for further clarification.
all characters listed in UTF8?
However, ICH data elements with the ICH “AN” data type may not always have an one-to-one mapping with the data type in ISO/HL7 27953-2 ICSR message standard. The representation of the data can vary across implementations. For Example ICH F.r.4 Normal Low Value and ICH F.r.5 Normal high Value. These data elements specify use of the ICH AN data type; however, the ISO/HL7 27953-2 message specification restricts allowable XML schema values using the HL7 xsi:type code designation Physical Quantity (PQ). The HL7 PQ data type is expressed as two XML schema attributes: value and unit; value has HL7 REAL data type and units are expressed as UCUM codes. For the use and information of the HL7 data type, please refer to the ISO/HL7 27953-2 Informative Annex F: HL7 Data Type Specification. In the Business Rule section for the related data elements, the ICH ICSR Implementation Guide provides information and examples for representing the ICH AN data type with HL7 data type in transmission.
3.2
November
Is it possible to use NI even if NI
No, only nullFlavors specified for each element in IG and Q&A document
(002)
2014
is not listed in allowed values?
are acceptable.
Because, the explanation of NI is
The value set of nullFlavor in Q&A supersede the value set stated in the
that No information whatsoever
IG.
can be inferred from this exceptional value. This is the ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 5/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) most general exceptional value. It is also the default exceptional value. 3.3
November
Does XML schema define default
The ISO/HL7 schema files automatically populate certain attributes
(004)
2014
values for some attributes?
with a default value, such as unit=’1’ for PQ data type and mediaType=’text/plain’ for ED data type. The ICSR sender should replace the default value with an appropriate value pertaining to the data being transmitted. For example, use the appropriate UCUM code for representing a unit of measurement for physical quantities (PQ) and media designation for encapsulated data (ED). To help reduce parsing errors, the sender should omit optional data element tags if there is no information to be transmitted. For example, patient age is an optional data element and the sender should omit the entire age observation class if no age value is known.
3.4
November
Is there anything senders should
Senders should refer not only to the ICH Implementation Guide and
(005)
2014
consider in creating XML files for
regional Implementation Guides but also its Appendices such as
ICSRs?
Reference instances, Technical Information and so on.
3.5
November
There is no guidance whether
In the ICH E2B(R3) ICSR messages, case sensitive form should be used
(007)
2014
case sensitive form or case
for codes.
insensitive form should be used
Please refer to regional guidance for more information about case
for codes in the ICH E2B(R3)
sensitivity.
ICSR messages. 3.6
November
Use of HL7 nullFlavors requires
Support for HL7 nullFlavor values, such as MSK (masked), NI (No
(008)
2014
implementation of very specific
Information) and UNK (Unknown) may vary across implementation.
business rules for parsing – not
Systems should be designed to receive process and re-produce a
necessarily as part of ICSR file
compliant message utilizing nullFlavors as defined in the ICH E2B(R3) IG.
validation. ICSR file validation is
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 6/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) checking appropriate HL7 nullFlavors by data element (datatype). Backend system parsing rules are different because they affect how data is actually displayed / queried in the database: EX: Date fields with a NI value cannot be parsed to a field structured for date/time. 3.7
November
A serious case was sent
a) Yes, the company should send a new message, updating the previous
(010)
2014
electronically by a company to a
report with the new information, indicating that the case is now non-
Regulatory Authority. Meanwhile,
serious.
due to follow-up information received at the company, this
b) No, the company should not send a new message to nullify the case in
case is now determined to be
the Regulatory Authority's database.
non-serious. c) Yes, this would be new information, and a follow-up report would be a) Should the company send a
appropriate utilizing the same safety report identifier.
new message indicating that the case is now non-serious? b) Should the company send a new message to nullify the case in the Regulatory Authority's database?
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 7/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) c) If the case becomes serious again, should the company send a new message with the same safety report identifier? 3.8
November
If a report is forwarded to a
a) and b) by definition a spontaneous report contains suspected adverse
(011)
2014
company by a Health Authority,
reactions (i.e., a possible causal relationship is suspected but not
should the company consider
established). However, there is no universally accepted definition for
that:
"possible" in the scale of causality assessment. It is therefore not
a) the Health Authority's
possible to provide a precise answer to this question. It is up to the
causality assessment is at least
company and receiver to define causality assessment method and classify
“possible”?
the case-reports accordingly.
b) the reporter’s causality assessment is also at least “possible”? 3.9
June
In the ISO 639-2 language code
For those languages where (T) and (B) codes are provided the (T) code
(028)
2016
list some languages appear twice
should be used in E2B(R3) messages.
with two different codes designated B and T: for instance Czech is either cze (B) or ces (T) where ‘B’ indicates ‘bibliographic’ and ‘T’ indicates ‘terminology’. In such instances is one of these correct (meaning that the other is incorrect) – if so, which, or is either OK? 3.10
June
Does data length provided in the
Data length provided in the IG represents the apparent number of
(029)
2016
IG (e.g. 5AN) represent data
characters. Please note some languages/characters require more than a
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 8/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) length (byte) or apparent
single byte for a character.
number of characters? In UTF-8, surrogate pairs and combining characters have longer data length (byte) than their apparent data length. 3.11
June
ISO 3166 Part 1 (alpha-2)
IG specifies use of ISO 3166 Part 1 (alpha-2). ISO 3166 Part 1 (alpha-2)
(038)
2016
country codes are provided in
supports use of country codes in E2B(R3) messages. This includes
the ISO web site.
“Officially assigned” country codes plus “EU” in the “Exceptionally
https://www.iso.org/obp/ui/#ho
reserved” category.
me
The “Unassigned” category should not be used. “Transitionally reserved”,
There are some categories like
“Indeterminately reserved” and “Formerly used” categories may be used
“Officially assigned codes” or
when appropriate, e.g., for legacy data.
N, C to H
“Other code types”. Does ICH accept “Officially assigned codes” only? Note: “EU” is categorized in “exceptionally reserved”
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 9/31
4. ICH E2B(R3) data elements #
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) 4.1
November
A man started medications
Following are abbreviated answer for the question and examples for
C.1.1,
(009)
2014
before his partner became
various scenario regarding parent and/or child/foetus.
C.2.r.3,
pregnant. But she has a miscarriage now.
D, a) Yes. In this case the ADR should be the miscarriage experienced by
E.i.9
the mother. a) Is the ADR a miscarriage? b) The patient should be the mother. b) Is the patient of the report the father or mother?
c) Yes. The route of administration should be how the father was given the suspect medication.
Is the route of administration how the father took the medicine?
Scenario 1: Miscarriage, drug administered to Mother Patient (D)
Mother
AE (E)
Miscarriage
Drug section (G)
Product taken by mother
Route of Administration (G.k.4.r.10)
Route administered to mother
Scenario 2: Miscarriage, drug administered to Father
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Patient (D)
Mother
AE (E)
Miscarriage
Drug section (G)
Product taken by father
Route of Administration
Use nullFlavor “UNK” in G.k.4.r.10.1
(G.k.4.r.10)
Describe information about father and
Page 10/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) mother in the narrative Additional Information on Drug (G.k.10.r)
3 (Drug taken by the father)
Scenario 3: foetus or breast-feeding infant is exposed to drug(s) through the mother and experienced adverse events/reactions Patient (D)
Infant/foetus
AE (E)
AE experienced by Infant/foetus
Drug section (G)
Product taken by mother
Route of Administration
This is usually an indirect exposure, such
(G.k.4.r.10)
as transmammary
Parent Route of Administration
Route administered to mother
(G.k.4.r.11) For a Parent-child / Foetus Report,
Mother’s information according to the user
Information Concerning
guidance for section D
the Parent (D.10) 4.2
November
How can I identify the primary
If no information on the primary source is available, section C.2.r should
C.1.3,
(014)
2014
source and the reporter
identify the Health Authority as the primary source.
C.2.r
qualification when an ICSR is
Field C.2.r.4 ‘Qualification’ should be populated with nullFlavor “UNK”.
forwarded by Health Authorities
Additionally, field C.1.3 ‘Type of report’ may be populated with a code of
with minimal or no information
“4” (Not available to sender (unknown), if appropriate.
on the primary source? 4.3
November
The conformance of C.1.5 is
Yes, a sender must enter date.
C.1.4,
(015)
2014
“Required”. Even if a sender has
If a sender has only first received information, the date of first received
C.1.5
only first received information
information and the date of most recent information are same, so a
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 11/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) and no follow-up information,
sender enter the date correspond to C.1.4 in C.1.5.
must a sender enter date in this field? 4.4
November
About E2B(R3) data element:
a) E.i.3.2 are mandatory elements and False is not a value allowed for
(019)
2014
E.i.3.2 Seriousness Criteria at
this data element. This mandatory data element should either be ‘true’ or
Event Level,
nullFlavor= ‘NI’. When the information is unknown or the event is not
E.i.3.2
serious, “NI” should be populated. a) How to describe “unknown” and “not serious”? What is
b) “Left blank” if not serious using the null flavor “NI”. All 6 criteria in
allowed value for this data
E.i.3.2 should be included in XML every time (even if a report is non
element?
serious). The following is an XML example.
b) How to describe allowed values and "left blank" in XML? 4.5
November
Here is scenario on E.i.4 and
Senders should populate the most accurate information known for each
E.i.4,
(020)
2014
E.i.5:
event. A blank field for start date or end date or both is acceptable if the
E.i.5
Reaction
E.i.4
E.i.5
information is not known to the sender. When a precise date is not
Sequenc
Start
End
available, the decision of whether to leave blank or an inferred date for a
e
date
date
given event should be left up to the sender’s clinical judgment. If the
Reaction
01-Feb-
02-Feb-
events are thought to be related (i.e., if event1 is a sign or symptom of
1
2010
2010
event2), it would be clinically reasonable to use the earliest start date or
Reaction
03-Feb-
-
latest end date, as relevant, for both events. However, a sender should
2
2010
Reaction
-
3
not infer dates unless there is a clear clinical rationale and this rationale 01-Jan-
should be stated in the case narrative.
2010
How to get the blank start date
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 12/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) and end date details. As per the IG, if we have to consider start date of first reaction and end date of last reaction, the output will not be correct. 4.6
November
How are the NullFlavors ‘NINF’
When empty data elements are transmitted, NullFlavors are used to code
(022)
2014
and ‘PINF’ implemented in ICH
the reason for the lack of data in a standardized manner. This allows for
E2B(R3)?
the creation of valid messages containing mandatory elements without
F.r.3.2
transmitting content. For ICH E2B(R3), the NullFlavors ‘NINF’ (negative infinity of numbers) and ‘PINF’ (positive infinity of numbers) are used only for the data element ICH E2B(R3) F.r.3.2 Test Result, and only when the element describes a range (e.g. data type IVL<…>) with an (unknown) infinity. For example, the concept of ‘equal or greater to 3’ can be represented asthe range from ‘3’ to ‘positive infinity’, e.g. any (unknown) number greater than 3. 4.7
November
User Guidance of F.r.3.2 Test
No, senders cannot add a qualifier symbol in this data element. This
023
2014
Result (value/qualifier) in the IG
data element captures the value (amount) for the test result. In ICSR
ver. 5.01 states that “A qualifier
message, this data element is represented in HL7 IVL_PQ data type
symbol can be added to the
which is a composite data type with multiple attributes. “Positive
value when appropriate. The
Infinity (PINF)” and “Negative Infinity (NINF)” null flavors are used to
supported qualifiers are ‘greater
express “Greater than” and “Less than” a specific value respectively.
than’, ‘less than’, ‘greater than
Followings are examples for test results with exact value, greater or
or equal to’ and ‘less than or
less than a specific value.
F.r.3.2
equal to’”. However allowed values are Numeric and null
Test Result = 10 (mg/dl)
flavor (NINF and PINF). Can
value="10" unit="mg/dl"/>
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 13/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) senders add a qualifier symbol (<, >, ≤, ≥)?
Test Result < 10 (mg/dl) Test Result <= 10 (mg/dl) Test Result > 10 (mg/dl) Test Result >= 10 (mg/dl)
4.8
November
If a value of test results does not
In such case, senders should enter the value and unit as unstructured
(024)
2014
have a suitable UCUM code or a
data in F.r.3.4.
F.r.3.4
unit (for example International Normalized Ratio, INR) or a unit of test results is unknown, how should the test results be entered? 4.9
November
a) How should re-administration
Answers to question a) through c) are summarized into the scenarios
E.i.4,
(026)
2014
data be entered after recovery
below:
E.i.7,
from AE, e.g., G.k.4.r.8 or
The data element (G.k.8) is not a repeatable data element and captures
G.k.4.r,
G.k.4.r repetition?
the action taken with the suspect drug as a result of the reaction(s) /
G.k.8,
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 14/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) event(s) as provided by the reporter of the information. This data b) When multiple dosage
element is a within the ‘parent’ instance of G.k Drug and only one action
information (G.k.4.r) is available
can be captured for each instance of G.k Drug.
for a drug, which dosage
Because this data element is not associated with its own ‘time’ element,
information should be used for
the relevant ‘time’ for G.k.8 Action(s) Taken with Drug is the onset of
G.k.8?
the reaction. Analysis of the dosage information records in G.k.4 in
G.k.9.i.4
combination with start date of the reaction/event in E.i.4 – Date of c) Is it possible to identify the
Start of the Reaction/Event – would enable the receiver of the
re-administration after drug is
information to determine the relevant G.k.4 Dosage Information
discontinued or after drug is
record associated with the reaction(s)/event(s).
temporarily stopped?
The information related to the outcome of the reaction(s)/event(s) is noted in E.i.7 - Outcome of Reaction / Event at the Time of Last Observation. If the reaction(s)/event(s) do not recur after reintroducing the drug, G.k.9.i.4 Did Reaction Recur on Re-administration? would be set to 2 (rechallenge was done, reaction did not recur) and E.i.7 – Outcome of Reaction / Event at the Time of Last Observation would be set to 1 = recovered/resolved. An example is provided in Appendix A.
4.10
November
Clarification was requested for
"1" should be selected for both suspected and confirmed counterfeit
E.i.2.1b,
(027)
2014
usage on coding reports of
products in G.k.10.r and the appropriate MedDRA term should be
G.k.10.r,
possible counterfeit drugs.
selected for E.i.2.1b. Any explanatory information should be included in
H.1,
case narrative. If new information is received to confirm the product is
H.3.r
not a counterfeit, then G.k.10.r should be changed appropriately as follow up. If the product is confirmed as a counterfeit, the sender should use the appropriate MedDRA code in H.3.r and explain in narrative. 4.11
June
When retransmitting an ICSR
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
As mentioned in the E2B(R3) implementation guide, the primary source
C.2.r.5,
Page 15/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) (030)
2016
received from another sender
of the information is the person who provided the facts about the ICSR.
such as a regulatory authority,
In case of multiple sources, the ‘Primary Source for Regulatory Purposes’
partner company, or other
(C.2.r.5) is the person who first reported the facts to the original sender,
source, which reporter should be
not retransmitter.
marked as 'Primary Source for
The primary source should be distinguished from senders and
Regulatory Purposes' (field
retransmitters. Information on the sender and retransmitters is captured
C.2.r.5)?
in section C.3. When retransmitting an electronic ICSR received from
C.3
another sender, such as a regulatory authority, partner company, or other source in E2B format, the Primary Source information in the initial transmission should reflect the reporter with first-hand information on the case and this should not be changed. The reporter identified as ‘Primary Source for Regulatory Purposes’ in the original transmission should remain unchanged in all subsequent retransmission of the case. 4.12
June
Which data element (F.r.3.4
Field F.r.6 is reserved for comments made by the reporter about the
F.r.3.4,
(032)
2016
Result unstructured data or F.r.6
results of tests and procedures.
F.r.6
Comments) is applicable for test
Unstructured findings from tests and procedures such as CT, MRI,
results such as comments on CT,
radiogram, etc. should be provided as free text in field F.r.3.4.
MRI, or radiogram? 4.13
June
The mother’s drug exposure has
It is appropriate to use G.k.6 to capture the earliest exposure during
(033)
2016
started prior to her pregnancy. Is
pregnancy, a clinical judgment should be used to choose the most
“G.k.6 Gestation period at time
appropriate value/unit.
G.k.6
of exposure” necessary to be populated on the child/foetus report and/or mother report? 4.14
June
Is “D.2.2.1 Gestation Period
In a foetus report, regardless the exposure from father or mother, the
D.2.2.1,
(034)
2016
When Reaction/Event Was
foetus age information should be provided in D.2.2.1. Information
D.10
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 16/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) Observed in the Foetus”
concerning the parent should be provided in section D.10.
necessary in the foetus report when drug was taken by father? 4.15
June
What is an appropriate age for
Section D.2 provides several options for reporting patient age
(035)
2016
newborn if an adverse drug
information.
reaction/event has been
The sender should select the most appropriate field based on the
developed during pregnancy but
information provided. Based on the information provided in the question,
just observed at time of
field D.2.3 may be the most appropriate field to report the patient age.
D.2
delivery? 4.16
June
What is an appropriate value for
Medical judgment should be used to assess the conceptual similarity of
E.i.2.1,
(036)
2016
“G.k.9.i.4 Did reaction recur on
the events. MedDRA codes do not need to be identical. [Refer to the most
G.k.9.i.4
re-administration?” if adverse
recent ICH MedDRATerm Selection: Points To Consider.]
drug reaction/event on readministration is not exactly the same as the one on previous administration? Ex) E.i.2.1 Reaction/event: liver disorder Re-administration: Aspartate aminotransferase increased 4.17
June
Certain units that are commonly
The unit “mg/mL” is now available on the constrained E2B Code List #25
2016
used to express concentration or
(file name E2B CL25 ich-dose-strength-unit.xml). The IWG will evaluate
strength of pharmaceutical
other UCUM units, singly and in combination, for possible inclusion in the
products are included in the
E2B constrained units list.
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
G.k.2.3.r.2b
Page 17/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) UCUM Mass Concentration Units but are missing from the E2B constrained term list. An example is mg/mL that might be used in E2B(R3) data element G.k.2.3.r.2b Strength (unit). Is it possible to add mg/mL to the terms available for strength units in ICSR XML messages? 4.18
June
How should “Decade” be
{Decade} in the IG should not be used. E2B(R3) EWG/IWG consulted
D.2.2b
2017
represented in data element
with UCUM and preferred notation is “10.a”. The code list #26 has been
D.10.2.2b
D.2.2b Age at Time of Onset of
updated accordingly.
Reaction / Event (unit) and D.10.2.2b Age of Parent (unit)? There is a discrepancy between the IG Value allowed and the code list #26, which one should be used?
5. Document attachment #
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) 5.1
June
The codesystem versions for the
Yes, a sender should update the codesystem version in ICSR messages
(037)
2016
E2B code lists used in the ICH
(xml files) for submission. Acceptable codesystem version(s) are
E2B(R3) reference instances are
designated by regulatory authorities in each region.
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 18/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) old compared to the latest version of the E2B code lists. Should a sender update the codesystem version appropriately?
6. The ICSR acknowledgement transaction No Q&A.
7. Appendices #
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) 7.1
June
If date/time is provided without
No, do not make this assumption. If date/time is provided as UTC
2017
timezone offset can I assume
exactly it would be expressed with a zero offset e.g.:
that it is UTC time? CCYYMMDDHHMM+0 CCYYMMDDHH+0 Note: This may need to be taken into consideration during data migration/conversion from E2B(R2) source data.
8. Q&As merged into the implementation guide These Q&As were incorporated into the documents included in the IG package (November 2016, Osaka).
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 19/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) 003
November
The lists of UCUM couldn’t be
Information about UCUM, including link to download the specification is
2014
found. Which website should be
available at: http://unitsofmeasure.org/trac/
referred to? 006
November
When ‘Z’ was added at the end
No, the examples described in Appendix I(C) are inappropriate. ‘Z’ should
2014
of time values as described in
not be added at the end of time values. XML Schema defines the Time
Appendix II I ISO 8601
Zone value as
Compliant XML Examples in the
9]{14,14}\.[0-9]+)([+|-][0-9]{”,4})?" />, and Appendix II (B) Time
IG ver. 5.01, parse error
Zone in the IG states that “The syntax is ‘CCYYMMDDHHMMSS.UUUU[+|-
occurred. Can senders use the
ZZzz]’ where digits can be omitted from right side to express less
representations of date and time
precision”.
such as 199411051315Z, 20090601231105.5Z, 20090601231105Z, 200906012331Z or 2009060123Z? 012
November
There are several references to
All references to M5 Identifiers in the Implementation Guide and
2014
M5 Identifiers in the E2B R3
associated technical documents should be replaced with ISO IDMP Terms
Implementation Guide, please
and Identifiers.
confirm these still apply? 013
November
It is not assumed that ‘In
No, it is not assumed that the country of the primary source is not
C.1.1,
2014
exceptional cases where the
available to sender and there is not any case that E.i.9 is used as
C.2.r.3,
country of the primary source is
alternative of Reporter’s Country Code.
E.i.9
not available to the sender’ described in User Guidance of
In this context, the description in User Guidance of C.1.1 ‘in exceptional
C.2.r.3. Is there any case that
circumstances where the country of primary source is unknown, the
E.i.9 is used as alternative of
country where the reaction occurred (E.i.9) should be used to indicate
Reporter’s Country code?
the country code’ is also inappropriate. A change of E.i.9 never change
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 20/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) Sender’s (case) Safety Report Unique Identifiers. 016
November
The Business Rule(s) of C.2.r.3
No, the description of Business Rule(s) of C.2.r.3 is inappropriate. E.i.9
C.2.r,
2014
Reporter’s Country Code in the
only allows a two character country code.
E.i.9
D.1
IG ver. 5.01 states that “When C.2.r.5 is populated ‘1’, nullFlavor is not allowed in this data element unless E.i.9 is populated without a nullFlavor”. However nullFlavor is not allowed in E.i.9 Identification of the Country Where the Reaction / Event Occurred. Can senders use nullFlavor in C.2.r.3? 017
November
NullFlavor value for D.1 stated in
The business rule for ICH D.1. Patient (name or initial) concerning the
2014
IG ver. 5.01 doesn’t match what
use of allowable null flavor values is incomplete. Senders should refer to
is stated in Appendix I (B)
table in section 5.6.2 nullFlavour for Fields Required in E2B(R3) and
Backwards and Forwards
follow guidance concerning use of additional null flavor values for D.1.,
Compatibility Recommendations
which include the use of: MSK, ASKU, NASK, UNK value options.
(BFC) ver. 2.00. The IG currently states that the nullFlavor value allowed is MSK and the BFC states that the nullFlavor values allowed are MSK, ASKU, NASK and UNK. 018
November
Appendix I (B) Backwards and
The business rule for D.7.1.r.3 or D.10.7.1.r.3 Continuing concerning the
D.7.1.r.3,
2014
Forwards Compatibility
use of allowable null flavor values is incomplete.
D.10.7.1.r.3
Recommendations (BFC) ver.
MSK, ASKU, NASK and UNK are allowed for D.7.1.r.3 and D.10.7.1.r.3.
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 21/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) 2.00 explains that “To upgrade to E2B(R3), ‘Continuing (patient
Senders should follow the guidance of upgrading to E2B(R3) or
or parent medical history)’ (i.e.,
downgrading to E2B(R2) in section 5.6.3 Null Flavour for Optional Codes
B.1.7.1d or B.1.10.7.1d in
and Dates concerning use of the14lavorlavour UNK for D.7.1.r.3 or
E2B(R2)) is provided with value
D.10.7.1.r.3.
‘3’ (unknown) in E2B(R2), the corresponding field should be
This correction is reflected in the BFC version 2.01 (modified in
provided in E2B(R3) with
November 2014).
the14lavorlavour (UNK)”. And the BFC also explains that “To downgrade to E2B(R2), ‘Continuing (patient or parent medical history)’ (i.e., D.7.1.r.3 or D.10.7.1.r.3 in E2B(R3)) has null flavor (UNK) in E2B(R3), the corresponding field in E2B(R2) should be provided with value ‘3’ (unknown)”. However, The IG currently states that the nullFlavor values allowed are MSK, ASK and NASK. 021
November
Test Result (code): ICH
2014
document states – “Optional, but
The conformance of F.r.3.1 is clarified as follows.
F.r.2, F.r.3.1,
required if F.r.2 is populated,
Optional, but required if F.r.2 is populated, and neither F.r.3.2 nor F.r.3.4
F.r.3.2,
and F.r.3.2 and F.r.3.4 is not
is populated”.
F.r.3.4
populated”. Whereas, EU
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 22/31
#
Date of
(# from
Approval
Questions
Answers
E2B (R3) data element
ver.1.1) implementation guide says – “Mandatory if F.r.2.2b is populated, and F.r.3.2 or F.r.3.4 is not populated.”. Similar discrepancy exists for F.r.3.2 and F.r.3.4. The explicit meaning of “OR” / “AND” used in this needs to be clarified. 025
November
The E2B IG implies the free text
The free text ‘Not specified’ or ‘Unknown’ should be expressed by using
G.k.7.r.1,
2014
field G.k.7.r.1 is optional,
nullFlavor.
G.k.7.r.2b
D.8.r.
however the business rules for G.k.7.r.2b. implies the use of a nullFlavor is mandatory. 031
June
The conformance of D.8.r.1
The conformance of D.8.r.1 in the current Implementation Guide is
2016
Name of Drug as Reported is
inappropriate. D.8.r Relevant Past Drug History can be left blank when no
“Required” and the business rule
information is obtained.
states that “Nullflavor=NA”
Technically, D.8.r.1 is required by the schema if any data element in
should be used when there is no
section D.8.r is used. Therefore the conformance of D.8.r.1 should be
previous exposure to a drug or
interpreted as Conditionally Required.
vaccine and no other nullFlavor
Null flavor = UNK is allowed when no information is available but need to
is allowed. Drug or vaccine
enter D.8.r.1.
exposure history may be unknown in most cases, but nullflavor=UNK is not allowed in this field. How should sender report such cases?
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 23/31
9. Q&As linked to the respective Sections of ICH E2B(R3) Guideline
Guidelines
Other ICH
Appendices
transaction
acknowledgement
4.0 The ICSR
attachments
3.5 Document
Data elements
Components
3: Essential
2: Background
1: Purpose
Guideline
Introduction
ICH E2B(R3)
3.4: ICH E2B(R3)
Sections of
1. Purpose 2. Background 3. Essential Components 1
3.2.3.2
I (A)
3.3.6 2
3.3.6
3
I(A)
4
I (D) I (G)
5
3.3.2
6
3.3.6
7 8 9
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
3.2.3
Page 24/31
10
3.3.7
11
3.2.3
Guidelines
Other ICH
Appendices
transaction
acknowledgement
4.0 The ICSR
attachments
3.5 Document
Data elements
Components
3: Essential
2: Background
1: Purpose
Guideline
Introduction
ICH E2B(R3)
3.4: ICH E2B(R3)
Sections of
4: ICH E2B(R3) Data elements 1
C.1.1 C.2.r.3 D E.i.9
2
C.1.3 C.2.r
3
C.1.4 C.1.5
4
E.i.3.2
5
E.i.4
I (G)
E.i.5 6
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
F.r.3.2
Page 25/31
7
F.r.3.2
8
F.r.3.4
9
E.i.4
Guidelines
Other ICH
Appendices
transaction
acknowledgement
4.0 The ICSR
attachments
3.5 Document
Data elements
Components
3: Essential
2: Background
1: Purpose
Guideline
Introduction
ICH E2B(R3)
3.4: ICH E2B(R3)
Sections of
I (G)
E.i.7 G.k.4.r G.k.8 G.k.9.i.4 10
E.i.2.1b G.k.10.r H.1 H.3.r
11
C.2.r.5 C.3
12
F.r.3.4 F.r.6
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 26/31
13
G.k.6
14
D.2.2.1
Guidelines
Other ICH
Appendices
transaction
acknowledgement
4.0 The ICSR
attachments
3.5 Document
Data elements
Components
3: Essential
2: Background
1: Purpose
Guideline
Introduction
ICH E2B(R3)
3.4: ICH E2B(R3)
Sections of
D.10 15
D.2
16
E.i.2.1
MedDRA PTC
G.k.9.i.4 17
G.k.2.3.r.2b
5 Document attachments 6 The ICSR acknowledgement transaction 7 Appendices 1
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
II (B)
Page 27/31
Appendix A Example for Q&A #4.9 Consider a patient starting a drug for smoking cessation. The dose is titrated upwards over 2 weeks.
After 4 weeks of use, the patient has onset of
nightmares. As a result, the drug is withdrawn and subsequently the reaction/event is resolved.
Initial
Withdraw due to Nightmares
Dose1 Dose2
Recovered
Dose3 Nightmares
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 28/31
Parent Element
Parent Value
C.1.5 Date of Most Recent Information for This Report
February 2nd
G.k.2 Drug Identification
k=1
‘QuitSmoking’
G.k.8 Action(s) Taken with Drug
k=1
'drug withdrawn’
Child Element
Child Value
k=1, r=1
January 1st: 0.5mg daily, orally, x 7 days
G.k.4.r Dosage and
k=1, r=2
January 8th: 1mg daily, orally, x 7 days
Relevant Information
k=1, r=3
January 15th -29th:1mg twice daily, orally (stopped)
G.k.9.i Drug-reaction(s) / Event(s) Matrix
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
i=1
January 29th: onset of (E.i.1) = Nightmares; (E.i.7=1-Recovered/Resolved)
Page 29/31
Follow up ICSR Subsequently two weeks later, the drug re-introduced (dose, duration and action taken are unknown) and the reaction/event recurred.
Follow-up
Withdraw due to Nightmares
Dose1
Readministered Dosage info unknown
Dose2 Dose3 Dose4 Nightmares
Nightmares Recurred (outcome: unknown)
Recovered
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 30/31
Parent Element
Parent Value
C.1.5 Date of Most Recent Information for This Report
March 15th
G.k.2 Drug Identification
k=1
‘QuitSmoking’
G.k.8 Action(s) Taken with Drug
k=1
'drug withdrawn’
Child Element
Child Value
k=1, r=1
January 1st: 0.5mg daily, orally, x 7 days
G.k.4.r Dosage and
k=1, r=2
January 8th: 1mg daily, orally, x 7 days
Relevant Information
k=1, r=3
January 15th -29th:1mg twice daily, orally (stopped)
G.k.9.i Drug-reaction(s) / Event(s) Matrix
k=1, r=4
February 13th: unknown, unknown
i=1
January 29th: onset of (E.i.1) = Nightmares; G.k.9.i.4 = 1 yes - yes (rechallenge was done, reaction recurred); (E.i.7=0-Unknown)
ICH guideline E2B (R3) - questions and answers EMA/CHMP/ICH/3943/2003
Page 31/31